New Lung Cancer Assay Ready for Prime Time

Zosia Chustecka

January 27, 2012

January 27, 2012 — A new assay that tests 14 genes can clarify the prognosis of patients who are diagnosed with early-stage nonsmall-cell lung cancer (NSCLC), and is more accurate than relying on clinical criteria, researchers report in a paper published online today in the Lancet.

The assay identifies patients with early-stage NSCLC who are at low, intermediate, and high risk for death within 5 years. This information can be used to decide on additional treatment, according to the researchers, headed by Michael Mann, MD, and David Jablons, MD, from the thoracic surgery division at the University of California, San Francisco (UCSF). The test is already available commercially as the Pinpoint Dx Lung Assay (Pinpoint Genomics Inc).

Although there have been studies of several different assays of this type in the past, they were all small. This one stands "head and shoulders above everything else" and is ready for "prime time" clinical use, according to John Minna, MD, professor of molecular pulmonology oncology at the University of Texas (UT) Southwestern Medical Center in Dallas.

In an editorial that will appear in a future print issue of the Lancet, Dr. Minna and Yang Xie, PhD, who is assistant professor of clinical sciences at the UT Southwestern Medical Center, write that this assay is "ready for widespread clinical testing."

Assay is Prognostic

This assay is prognostic; it can help clinicians clarify the prognosis of patients with early-stage NSCLC, Dr. Minna explained in an interview. The initial validation study was conducted in patients with stage I NSCLC; further validation studies were conducted in patients with stage I, II, or III NSCLC.

Many of these patients with early-stage NSCLC are treated with surgery alone, he said. For stage I NSCLC, the use of chemotherapy after surgery remains controversial; studies have not shown a clear benefit and the treatment is associated with adverse effects and an increase in cost.

With many solid tumors, the expectation is that if you catch it early, resection should be curative, Dr. Minna explained. But in the case of lung cancer, unlike many other cancers, survival is rather poor — only about 50% to 60%, he noted.

"This happens because even if the resected tumor is small, in many cases the cells have already metastasized to other sites," he continued. There is no way to identify when this happened, he pointed out. "If you look under the microscope, you won't see anything."

In such situations, the assay can be helpful. By identifying gene-expression patterns associated with a low, medium, and high risk for death, the assay can identify patients whose early-stage lung cancer has already likely metastasized and who can benefit from additional therapy such as chemotherapy, he explained.

The theory underlying this research, Dr. Minna said, is that tumors that are more aggressive and are likely to have already metastasized will have a different gene-expression pattern than tumors that are localized. This is why the study showed that certain gene-expression patterns were highly correlated with different degrees of risk for death. However, whether the 14 genes in this assay are actually involved in driving the tumor is unclear, he added.

The research on driver-gene mutations in lung cancer, which has resulted in specific tests for gene mutations that are predictive assays — such as the test for EGFR mutations that predicts response to erlotinib and that for the ALK fusion that predicts response to crizotinib — does not apply in this situation. Those are predictive assays, whereas the new assay is prognostic, he explained.

In the real word, he can envision the 2 types of assays being used alongside one another. The 2 tests could be conducted on the same piece of lung tissue removed at the time of surgery. In fact, this is one of the advantages of the new assay, Dr. Minna noted: It is carried out on paraffin-embedded specimens, whereas previous prognostic assays have needed frozen tissue samples, which can cause practical problems.

Testing the New Assay

The assay was developed by UCSF researchers, and then licensed to and developed further at Pinpoint Genomics (based in Mountain View, California). It tests for 11 cancer-related target genes (BAG1, BRCA1, CDC6, CDK2API, ERBB3, FUT3, IL11, LCK, RND3, SH3BGR, WNT3A) and 3 reference genes (ESD, TBP, YAP1).

The initial test was conducted at UCSF in 361 patients with nonsquamous NSCLC. In the cohort, 66% had stage I disease, 12% had stage II disease, 17% had stage III disease, and 3% had stage IV disease. For 2%, disease stage was undetermined.

The first validation study was conducted independently on a masked cohort of 433 patients, all with stage I NSCLC, at several community Kaiser Permanente Northern California hospitals. The assay predicted that 5-year overall survival would be achieved by 71% of patients identified as being at low risk, 58% identified as being at intermediate risk, and 49% identified as being at high risk.

The second validation study was conducted at several leading Chinese cancer centers that are part of the China Clinical Trials Consortium. Of the 1006 patients with NSCLC, 47% had stage I disease, 22% had stage II disease, and 26% had stage III disease; disease stage was undetermined in only 1%. The assay predicted that 5-year overall survival would be achieved by 74% identified as being at low risk, 57% identified as being at intermediate risk, and 45% identified as being at high risk. These figures are nearly identical to those obtained in the first validation study.

The assay performed better than standard criteria, such as sex, age, tumor size, and even disease stage, the researchers note. It even outperformed National Comprehensive Cancer Network guidelines to identify high-risk patients with stage I disease, they add.

"This assay provides prognostic differentiation of patients with early-stage disease and might be helpful in the identification of the most appropriate application of treatment guidelines to improve clinical outcomes," the authors conclude.

Next Step: Clinical Trial

The next step the researchers are planning is a prospective clinical trial in patients identified as being at high risk; they will be randomized to either observation or chemotherapy. This trial will "directly test the effectiveness of the application of guidelines for adjuvant treatment on the basis of this molecular enhancement of risk stratification in patients with stage I disease," they explain.

However, the results will not be available for some time — the accrual alone for this trial will take 5 to 7 years and there will be additional years for follow-up, they note.

In the meantime, the authors suggest that this new assay "might provide additional, validated prognostic information to clinicians as they consider therapeutic choices that may improve outcomes for their patients."

Several of the authors report a consulting relationship with Pinpoint Genomics Inc. Both editorialists report being involved in a patent application for a lung cancer prognosis signature based on nuclear hormone receptors.

Lancet. Published online January 27, 2012. Abstract

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